Gastroenterology Hepatology

Long-term complications of liver transplantations

How can I be sure that the patient has complications post liver transplantation?

Signs and symptoms usually found

Common complications of post-liver transplantation include renal dysfunction in up to 18% of patients 5 years after liver transplantation. Biliary strictures/leaks are noted in 4% to 15% in deceased donor liver transplantation and in living related transplantation, up to 30%.

The risk of malignancy is 2 to 4 times higher in liver transplant patients. Malignancies account for up to 30 % of late deaths in liver transplant recipients. The most common malignancies are non-melanoma skin cancer, lymphoproliferative disease, colorectal cancer, lung cancer, and oropharyngeal and urological tumors.

Recurrent disease is common, with hepatitis C up to 30% in patients with graft dysfunction. Hepatitis B is less common: 2% to 5% is due to nucleos(t)ide and HBIG (hepatitis B immune globulin). Recurrent PSC/PBC (primary sclerosing cholangitis/primary biliary cirrhosis) is reported in up to 15% to 20% of patients but rarely result in graft failure. Pneumonia; sepsis; gastrointestinal, skin, and urinary infections account for up to 70% of infections post liver transplant.

What is the usual constellation of clinical features?

Renal dysfunction is usually asymptomatic, but it can be manifested by the development of peripheral edema/anasarca and early post-transplant ascites.

Serum creatinine of more than 1.8 mg/dL is concern for consideration of management changes. Biliary strictures are associated with elevated bilirubin, gamma-glutamyl transpeptidase (GGTP), alkaline phosphatase, and mild elevation of AST/ALT (aspartate aminotransferase/alanine aminotransferase). Clinical signs of jaundice may be present and pruritus is rare. Bile leaks are suspected with right upper quadrant pain, fevers, chills, elevated WBCs, and jaundice.

De novo malignancy is typically discovered with routine healthcare screening for colon, prostate, breast, uterine, and skin cancers. Recurrent hepatitis presents with elevations of transaminases and bilirubin, whereas recurrent primary biliary cirrhosis notes abnormalities of alkaline phosphatase, GGTP, and bilirubin.

Infectious complications correlate with respiration symptoms (pneumonia), dysuria (UTI), sepsis (hypotension, fevers, chills), and abdominal pain (abdominal abscess). (See Table I.)

Table I.

Complications of liver transplantation
Complication Features  Other diseases 
Renal dysfunction Rise in Cr, edema, anasarca  Severe malnutrition with hypoalbumia
Biliary stricture/leak Rise in alkaline phosphatase, GGTP, bilirubin, fevers, fluid collection in abdomen  Sepsis of intra-abdominal source
Malignancy New skin lesion   None
Recurrent disease Rise in ALT, AST, alkaline phosphatase, bilirubin  Acute/chronic cellular rejection
Infection Elevated WBC, fever, chills, rise in liver tests  Biliary complication

A tabular or chart listing of features and signs and symptoms of common complications

See Table I.

How can I confirm the diagnosis?

What tests should be ordered first?

Renal dysfunction. Serum Cr, BUN, measurement of urinary volume, UA

Biliary stricture/leak. Serum bilirubin, alkaline phosphatase, GGTP, U/S (dilated ducts); leaks (U/S for fluid collection)

Malignancy. Breast – mammogram; prostate – PSA; colon – colonoscopy; skin – skin examination; lung – CXR; oral/pharyngeal – oral examination

Recurrent disease. Hepatitis – B/C, ALT/AST, bilirubin; PBC/PSC – alkaline phosphatase, bilirubin; autoimmune hepatitis – AST/ALT, bilirubin

Infection. WBC, blood/urine cultures

What tests should be used to confirm the initial tests?

Renal dysfunction. Urinary sodium, Cr, U/S (kidney size)

Biliary stricture/leak. MRCP, ERCP (stricture); CT abdomen (leak)

Malignancy. Breast – U/S breast; prostate – biopsy; colon – biopsy of any lesions; skin – biopsy; lung – CT of chest; oral/pharyngeal – biopsy any lesion

Recurrent disease. Hepatitis – B/C, liver biopsy; PBC/PSC – MRCP-ERCP; autoimmune hepatitis – liver biopsy

Infection. Imaging studies of anatomical areas of concern, CXR, CT, or MRI

What tests are useful if diagnosis is still in doubt?

Renal dysfunction. Nephrology consult

Biliary stricture. ERCP/PTC; biliary leak – aspiration of fluid collection with analysis for bilirubin, WBC, culture

Malignancy. Biopsy of any suspected lesion

Infection. Obtain tissue diagnosis of infection with biopsy or surgery of any lesions.

What other diseases, conditions, or complications should I look for in patients post liver transplantation?

  1. Recurrence of primary liver diseases. HBV, HCV, autoimmune hepatitis, alcohol, and hepatocellular carcinoma. Typically, initial presentation would be elevations of liver tests.

  2. Renal dysfunction. Due to drug-to-drug interaction with immunosuppression medications, NSAIDS, diabetes, or long-term calcineurin inhibitor use. Review of medications and consideration of change in immunosuppression medications may be helpful.

Major risk factors for patients post liver transplantation

Renal dysfunction. Calcineurin inhibitors (cyclosporine/tacrolimus) and hepatorenal syndrome prior to transplantation are the major risk factors for renal dysfunction post liver transplant. Other factors include advanced age, hepatitis C, female gender, hypertension, diabetes mellitus, and acute renal failure immediately post operatively.

Biliary complications. Biliary stricture risk factors include hepatic artery thrombosis and ischemic injury to the bile ducts, too tight, of biliary anastomosis reconstruction at time of surgery. Bile leaks are associated with T-tube migration or removal and poor healing of anastomosis.

Malignancy. Risk factors for de novo malignancy involve immunosuppression for post-transplant lymphoproliferative disease (EBV-driven), excessive sunlight exposure for skin cancers, alcohol and tobacco use for head and neck cancers, and smoking for lung cancers.

Recurrent disease. Over immunosuppression (which may include treatment for multiple bouts of rejection) increases the risk of recurrent hepatitis B and C. Under immunosuppression increases the risk of recurrent autoimmune hepatitis, PBC, and PSC. Patients treated with tacrolimus have a higher risk of recurrent primary biliary cirrhosis.

Infection. Risks in the immediate post-operative period involve immunosuppression for viral diseases (cytomegalovirus [CMV], Epstein-Barr virus [EBV], herpes simplex virus [HSV]). Bile leaks are associated with intra-abdominal bacterial abscess. Retransplantation and multiple vascular lines are associated with fungal infections. Infections that occur more than one year post transplant are cholangitis, pneumonia, and sepsis. The most common organisms are Enterococcus spp., Escherichia coli, and cytomegalovirus.

What is the right therapy for the patient with post liver transplantation?

N/A

What is the most effective initial therapy?

Renal dysfunction. Calcineurin inhibitor (CNI) medications remain the principle cause of renal dysfunction. Initial therapy with reduction of CNI (50-75% decrease in dose) with addition of an adjuvant agent (mycophenolate mofetil, MMF) or mTOR inhibitor (sirolimus/everolimus) has improved GFR at up to 50%.

Biliary stricture. Anastomosis strictures are typically treated with ERCP-guided (endoscopic retrograde cholangiopancreatography) balloon dilation with biliary stent placement requiring 2 to 3 sessions with success rates of 70% to 100%. Nonanstomosis strictures that are usually intraheptic are treated by PTC with dilation and biliary stents with success of up to 50%. Biliary leaks at the anastomosis site or the cut edge of living related transplant respond to endoscopic treatment with sphinterotomy and temporary stent placement at up to 90%.

Malignancy. Treatment of specific oncological disease is usually directed by a multidiscipline team that may include surgical, chemotherapy, and radiation treatments. No data exists regarding changes in dosing of immunosuppression and outcomes. However, generally speaking, immunosuppression is reduced with chemotherapy. Patients with post-transplant lymphoproliferative disease usually have immunosuppression stopped.

Recurrent disease. Hepatitis B recurrence is treated by nucleos(t)ide exchange to treat viral breakthrough. Lamivudine resistance is treated with adefovir or tenofovir. Recurrent autoimmune hepatitis can be treated by increasing immunosuppression by adding another medication, such as azathioprine, mycophenolate mofetil, or sirolimus/everolimus. Recurrence of PBC or PSC treated with ursodiol improves liver tests, but whether it decreases the risk of advancing fibrosis is not known.

Infection. Anatomically and blood-specific cultures and sensitivities will guide antimicrobial and viral infections. Cytomegalovirus is treated with valcyclovir and herpes viral infections with acyclovir. Broad spectrum antibiotics are used for bacterial pneumonia and intra-abdominal infections.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

What therapy is best if initial therapy fails?

Renal dysfunction. Conversion from a CNI to mTOR regime resulted in an improvement of GFR by up to 30%. Initial treatment with antibody induction immediately post-transplant with delayed CNI up to 2 weeks later showed a difference at 1 year post transplant of a GFR change of –13 mL/m compared to –23.6 mL/m in patients without induction antibody use.

Biliary Strictures. If initial therapy fails (ERCP or PTC), biliary strictures can be corrected with revision to Roux-en-Y anastomosis (for duct-to-duct strictures). Intrahepatic strictures are more difficult to treat and may require indefinite biliary stents. Continued biliary leaks also require surgical revision (typically with a Roux-en-Y biliary conversion) for a duct-to-duct anastomosis leak.

Malignancy. Oncology should direct all initial and subsequent treatments.

Recurrent disease. Little to no other treatment options are available medically, outside of the above-mentioned therapies. However, if graft dysfunction and decompensation develops, consideration for retransplantation is the last option.

Infection. Judicious use of infectious disease consultation is encouraged with less than optimal initial treatments.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

What side effects or complications should I expect from therapy?

Renal dysfunction. Side effects of MMF include diarrhea, PUD, abdominal pain, and leukopenia at up to 20% of the time. mTOR inhibitors prime side effects are hyperlipidema, proteinuria, anemia, and arthalgias. Development of ESRD requiring dialysis occurs in up to 18% of patients 10 years post liver transplant. Those who develop ESRD have a 27% survival rate of 3 years after starting dialysis.

Biliary stricture. Inherent complications of ERCP (pancreatitis, cholangitis) or side pain at the skin site of an internal/external drain are the common complications of treatment. Biliary leaks result in complications of perihepatic fluid collection/abscess. Those patients who fail endoscopy or interventional radiology treatments require surgical revisions (anastomosis stricture, conversion to a Roux-en-Y hepaticojejunostomy) or biliary leak local repair, or conversion to Roux-en Y anastomosis.

Malignancy: Well-defined side effects from chemotherapy, radiation, and surgery are no different for the liver transplant patient. If immunosuppression is reduced or stopped, the risk of allograft rejection is noted to be from 25% to 50%.

Recurrent disease. Caution should be used with adefovir or tenofovir in transplant patients with renal dysfunction in the treatment of hepatitis B. Inherent side effects with interferon are noted in post-transplant patients. However, the risk of anemia with ribavirin use is noted in up to 60% of patients. Thrombocytopenia, leukopenia, and higher infection rates can occur with the addition of a second immunosuppression medication for recurrent autoimmune hepatitis.

Infection. Secondary complications of C. difficile are common in post–liver-transplant patients treated with multiple antibiotics. Treatment of fungal infections, especially with amphotericin, is associated with development of renal dysfunction.

Listing of these, including any guidelines for monitoring side effects.

N/A

How should I monitor the patient with complications post liver transplantation?

Renal dysfunction. Monitoring with serum creatinine and BUN with consideration of changing immunosuppression with a Cr of more than 1.8 dl/L.

Biliary Strictures. Progressive rise in bilirubin and alkaline phosphatase is suggestive of a biliary stricture. After therapeutic intervention, liver tests should improve rapidly (<1 week). Biliary leak: If patient has an intra-abdominal drain, the output should rapidly decrease. Liver tests and WBC will also improve at stent placement across the biliary leak.

Malignancy. Monitoring of liver tests, CBC, and renal function during treatment on a weekly basis should be incorporated to monitor for complications.

Recurrent disease. Evaluation of liver tests during treatment of recurrent disease for all causes at weekly to monthly intervals is preferred.

Infection. Monitoring liver tests, CBC, renal function, and for sepsis (positive blood cultures and hemodynamic change) should be done.

What's the evidence?

Ojo, A, Held, P, Port, F. "Chronic renal failure after transplantation of a nonrenal organ". N Engl J Med. vol. 349. 2003. pp. 931-40.

Charlton, M., Wall, W, Ojo, A. "Report of the First International Liver Transplantation Society Expert Panel Consensus Conference on Renal Insufficiency in Liver Transplantation". Liver Transplant. vol. 15. 2009. pp. S1-S34.

Sharma, S, Gurakar, A, Jabbour, N. "Biliary strictures following liver transplantation; past, present and preventive strategies". Liver Transplant. vol. 14. 2008. pp. 759-69.

Londono, M, Balderramo, D, Cardenas, A. "Management of biliary complications after orthotopic liver transplantation: the role of endoscopy". World J Gastroenterol. vol. 14. 2008. pp. 493-7.

Watt, K, Pedersen, R, Kremers, W. "Long-term probability of and morality from de novo malignancy after liver transplantation". Gastroenterology. vol. 137. 2009. pp. 2010-17.

Watt, K, Pedersen, Kremers, W. "Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study". Am J Transpl. vol. 10. 2010. pp. 1420-7.

Berenguer, M, Prieto, M, Rayon, J. "Natural history of clinically compensated HCV-related graft cirrhosis following liver transplantation". Hepatology. vol. 32. 2000. pp. 852-8.

Liermann Garcia, R, Evangelista Garcia, C, McMaster, P. "Transplantation for primary biliary cirrhosis: retrospective analysis of 400 patients in a single center". Hepatology. vol. 33. 2001. pp. 22-7.

Fishman, J. "Infection in solid-organ transplant recipients". N Engl J Med. vol. 357. 2007. pp. 2601-14.

Aberg, F, Makisalo, H, Hockerstedt, K. "Infectious complications more than 1 year after liver transplantation: a 3 -decade nationwide experience". Am J Transpl. vol. 11. 2011. pp. 287-95.

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